Comella P, Lorusso V, Casaretti R, De Lucia L, Cartení G, Manzione L, Mancarella S, De Lena M, Comella G
Division of Medical Oncology A, National Tumor Institute, Naples, Italy.
Tumori. 1999 Nov-Dec;85(6):465-72. doi: 10.1177/030089169908500608.
Methotrexate (MTX) and leucovorin (LV) can enhance the cytotoxicity of 5-fluorouracil (5FU) by modifying its metabolic pathway inside target cells. Some preclinical studies and clinical trials have suggested that the concurrent or sequential double modulation of 5FU by means of MTX and LV may give a higher activity than single biochemical modulations. The purpose of our phase II study was to assess the activity and toxicity of a biweekly regimen including MTX, levo-LV and 5FU in colorectal cancer patients.
From July 1994 to May 1997, 100 consecutive patients affected by advanced or metastatic colorectal carcinoma were given MTX, 750 mg/m2 iv (2-h infusion) on day 1, and levo-LV, 250 mg/m2 iv (2-h infusion) followed by 5FU, 800 mg/m2 iv bolus on day 2, every two weeks. Patients were treated until complete response or progressive disease was documented, or for a maximum of 16 courses.
Among 97 eligible patients, 5 complete and 25 partial responses were obtained, giving an overall response rate of 31% (95% exact confidence limits, 22-41%). Response rate was significantly higher in patients with a good (ECOG scale 0) than with a poor (ECOG scale 1 or 2) performance status (40% versus 17%, P <0.02). Median time to treatment failure was 27 weeks, median survival time was 63 (95% confidence limits, 54-71) weeks, and 2- and 3-year probability of survival were 34% and 12%, respectively. Performance status was the only pretreatment characteristic significantly affecting the outcome of patients. Indeed, median survival time was 94 weeks for patients with a performance status = 0 and 37 weeks for patients with a performance status > or = 1 (P<0.05). Toxicity of the treatment was low and manageable; grade 3 to 4 leukopenia affected 8% of patients, whereas grade 3 diarrhea and mucositis occurred in 5% and 4%, respectively.
The double biochemical modulation of 5FU by MTX and levo-LV is at least as effective as, and probably more effective than, the single modulation by MTX or by LV. It may therefore represent a therapeutic option for the palliative treatment of patients with advanced colorectal carcinoma.
甲氨蝶呤（MTX）和亚叶酸钙（LV）可通过改变5-氟尿嘧啶（5FU）在靶细胞内的代谢途径来增强其细胞毒性。一些临床前研究和临床试验表明，通过MTX和LV对5FU进行同步或序贯双重调节可能比单一的生化调节具有更高的活性。我们II期研究的目的是评估一种每两周一次的方案（包括MTX、左亚叶酸钙和5FU）对结直肠癌患者的活性和毒性。
从1994年7月至1997年5月，100例连续的晚期或转移性结直肠癌患者在第1天接受MTX，750 mg/m²静脉注射（2小时输注），然后接受左亚叶酸钙，250 mg/m²静脉注射（2小时输注），随后在第2天接受5FU，800 mg/m²静脉推注，每两周一次。患者接受治疗直至记录到完全缓解或疾病进展，或最多接受16个疗程。
在97例符合条件的患者中，获得了5例完全缓解和25例部分缓解，总缓解率为31%（95%确切置信区间，22 - 41%）。体能状态良好（ECOG评分为0）的患者缓解率显著高于体能状态差（ECOG评分为1或2）的患者（40%对17%，P <0.02）。治疗失败的中位时间为27周，中位生存时间为63（95%置信区间，54 - 71）周，2年和3年生存率分别为34%和12%。体能状态是唯一显著影响患者预后的预处理特征。实际上，体能状态 = 0的患者中位生存时间为94周，体能状态≥1的患者中位生存时间为37周（P <0.05）。治疗的毒性较低且可控；3 - 4级白细胞减少影响8%的患者，而3级腹泻和黏膜炎分别发生在5%和4%的患者中。
MTX和左亚叶酸钙对5FU的双重生化调节至少与MTX或LV的单一调节一样有效，可能更有效。因此，它可能代表晚期结直肠癌患者姑息治疗的一种治疗选择。
